We propose a theoretical approach to a variety of problems in peptide biochemistry. Flexibility, the conformational distributions and their dependence on solution environment govern many of the observed differences in biological activity between linear peptides and their cyclized analogs. The development of new theories capable of handling these problems and critical evaluation of our methods for peptide-based systems comprise the focus of the proposed studies. A program with two complementary methodological approaches will continue to be pursued. Analytic methods using integral equations to produce free energy (or reversible work) surfaces implicitly including solvent effects will continue to be developed. Such methods have led to a free energy molecular mechanics approach which combines the ease of traditional molecular mechanics with a realistic model of solvent effects including solvation shells and dielectric screening for small peptide systems. Parallel development of new simulation methods serves to check the approximate analytic methods and to study more complicated systems inappropriate for our current theories. Work will continue on the conformational distribution of cyclized enkephalin analogs and both cyclic and linear superpotent analogs of alpha- melanocyte stimulating hormone. New experimental data on peptidic ribonucleotide reductase inhibitors and alpha-melanocyte stimulating hormone will be used as a test of our methods in comparison with high field NMR results. We believe this offers a unique combined focus to approach this aspect of peptide conformation problems.